Gadekar et al., [J. Med. Chem. 11, 811-814 (1968)] prepared a series of 1-cyano-3-substituted-guanidines which exhibited antihypertensive and hypotensive activities. An undesirable action frequently found with guanidine and cyanoguanidine compounds is that of ganglionic blockade and it was noted that the nature of the 3-substituent is critical for obtaining hypotensive effects without ganglionic blockade. The desirable profile appeared to be restricted to a series of 3-lower alkyl derivatives in which the carbon alpha to nitrogen is branched. Such structures as (II) are disclosed in U.S. Pat. No. 3,308,022. ##STR3##
Certain of these compounds are potent hypotensive agents, and the preferred compound is guancydine (II, R.dbd.CH.sub.3) which has been studied in animals and man. Guancydine has several undesirable side effects (Drugs of the Future, Vol. III, No. 4, 1978, pp. 291-294 and references therein, Martindale's The Extra Pharmacopeia, 27th Edition (1977) p.1765) including urinary retention, oedema, sinus tachycardia, weight gain, gynaecomastia and nausea. None of the disclosed compounds contain fluorine substituents. Due to the physiochemically distinct yet sterically similar characteristics of hydrogen and fluorine, fluorine substitution for hydrogen in drug moieties may alter the physical and biological properties often with enhancement of the desired activity and has resulted in the development of many new drugs. Examples of fluorinated drugs with enhanced properties are to be found in the treatment of many diseases. The following references to the Merck Index (9th Edition) are representative; triamcinolone #9279, dexamethasone #2899, fluoxymesterone #4070, flurazepam #4078, fenfluramine #3902, and 5-fluorouracil #4067. Such substitution may result in unexpected changes in potency, rate of absorption, duration of action, and the elimination of undesirable side effects.
The compounds of formula (I) possess useful pharmacological properties, e.g. they exhibit antihypertensive, vasodilator and dopaminergic activities. It will be obvious to those skilled in the art that stereoisomers, racemates and optically active forms of any of the compounds of formula I are possible and such forms are comprehended within the scope of the invention. By the terms "lower alkyl" and "lower alkenyl" as used in defining "R" groups are meant such groups containing no more than about six (6) carbon atoms. Particularly satisfactory from the point of view of antihypertensive activity is that class of compounds wherein R.sub.2 and R.sub.3 are methyl and R.sub.1 is an alkyl group containing fluorine; and the compound of formula I wherein R.sub.1 is CF.sub.3 CH.sub.2 -- and R.sub.2 and R.sub.3 are CH.sub.3 is a preferred species, exhibiting pronounced antihypertensive effect even after 24 hours as determined by its effects on the blood pressure of Spontaneously Hypertensive Rats (SHR).
The compounds of this invention are prepared by reacting an amine of formula (III) with sodium dicyanamide in an appropriate solvent (such as n-butanol) at elevated temperatures, preferably at from about 90.degree.-120.degree. C. for a period of from about 12 to 120 hours. The reaction proceeds according to the following equation: ##STR4##
The amines of formula (III) can be prepared by a number of methods. Many suitable such amines are known in the prior art and related novel amines can be prepared by techniques completely analagous to those employed in the art. Various preparatory embodiments (wherein "X" is halogen) are illustrated diagramatically in Schemes 1-6 below. ##STR5##